FI88025C - FREQUENCY REQUIREMENT FOR THERAPEUTIC ACTIVATION OF ACTIVE VINYL PHENOL - Google Patents

Abstract

Vinylphenol derivatives of the formula I <IMAGE> where A and R1 to R7 have the meanings stated in claim 1 and in the description, and their physiologically tolerated salts, drugs prepared from these, and their use for the treatment of various disorders of the skin, the mucous membranes and the internal organs, and of rheumatic disorders.

Description

0 8 025

A process for the preparation of therapeutically active vinylphenol derivatives

The invention relates to a process for the preparation of novel vinylphenol-5 derivatives.

It is known from DE patent application 28 54 354 and DE patent application publication 32 02 118 that vinyl benzoic acid derivatives have pharmacological effects in the local and systemic therapy of neoplasts, acne, psoriasis and other dermatological diseases. However, their effect is not always satisfactory, mainly due to adverse side effects.

EP-A-58 370 describes vinylthio-phenol derivatives. Thiophenols And thioethers are chemically bridged and their physiological properties are quite different from those of phenols and their derivatives, for example in terms of oxidation-reduction properties. Thiophenols are unstable and difficult to handle.

It has now been found that vinylphenol derivatives of formula (I) CH3 CH3 CH3 · ζο-Νχ ',; CH3 CH3 ^ OR2 wherein R1 is a hydrogen atom or a C1-4 alkanoyloxy group and R2 is a hydrogen atom, a C1-4 alkyl group or a C1-4 alkanoyl group optionally substituted by a carboxyl or C1-4 alkoxycarbonyl group, or R1 and R2 together represent a group - CH2-O-, as well as their physiologically acceptable salts, have a better spectrum of action and less toxicity, as well as a broader therapeutic range.

2 1'8 O 2 B

Typical examples of compounds to be prepared according to the invention are: 1- (4-hydroxyphenyl) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) propene, (4-methoxyphenyl) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) propene, 1- (4-ethoxyphenyl) -2- (5, 6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) propene, 1- (4-propyloxyphenyl) -2- (5,6,7,8-tetrahydro-5,5 , 8,8-10 tetramethyl-2-naphthalenyl) propylene, 1- (4-butoxyphenyl) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) Propylene, 1- (4-isopropyloxyphenyl) -2- (5,6,7,8-tetrahydro-5.5,8,8-tetramethyl-2-naphthalenyl) propylene, 1- (4-tert-butyloxyphenyl) -2- (5 , 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) propene, 1- (4-formyloxyphenyl) -2- (5,6,7,8-tetrahydro-5,5,8,8 tetramethyl) -2-naphthalenyl) propylene, 1- (4-acetoxyphenyl) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) propene, 1- (4-propionyylioksifenyyli) -2- (5,6,7,8-tetra hydro-5.5.8,8-tetramethyl-2-naphthalenyl) propene, 4- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-propenyl ] Phenoxyacetic acid methyl ester, 4- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-propenyl] phenoxyacetic acid ethyl ester, 4- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-propenyl] phenoxyacetic acid, 5- [1- (2- (5,6,7,8 -tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-propenyl] -1,3-benzodioxole, 1- (3,4-diformyloxyphenyl) -2- (5,6,7 , 8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) propene, 1- (3,4-diacetoxyphenyl) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthalenyl) propylene, 35 1- (3,4-dipropionyloxyphenyl) -2- (5,6,7,8-tetrahydro-3 38025 5.5.8.8-tetramethyl-2-naphthalenyl) propene and 1- (3, 4-Dibutyloxyphenyl) -2- (5,6,7,8-tetrahydro-5.5.8,8-tetramethyl-2-naphthalenyl) propylene.

Compounds of formula I may be prepared by reacting a carbonyl compound of formula (II) ch3 ch3 ch3 ch3 ch3 with a phosphorus compound of formula (III) according to the Wittig-Horner reaction.

\ 0 ORJ

r2 ° ~ \ VCH2 “" n 4

\ = / N0R4 III

Wherein R1 and R2 are as defined above and R3 and R4 are C1-4 alkyl. Suitably the reaction is carried out in a solvent for Wittig-Horner reactions in the presence of customary basic compounds.

The Wittig-Horner reaction takes place in a temperature range of -20 to 100 ° C, expediently in the range of 20 to 50 ° C.

: - The reaction can be carried out at normal pressure or in a closed vessel under elevated pressure, possibly by heating to a given temperature range.

This reaction may be carried out using a diluent or solvent present, for example a lower saturated dialkyl ether, a dialkyl glycol ether or a cyclic ether such as diethyl ether, ethyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran.

• j S G 2 S

or dioxane, an aromatic hydrocarbon such as benzene or an alkylbenzene such as toluene or xylene, or a saturated aliphatic hydrocarbon such as hexane, heptane or isooctane, a lower aliphatic ketone such as acetone, motile ethyl ketone, methyl methyl ketone or methyl - or diethylformamide, or mixtures of said solvents. Preferably, cyclic ethers such as dioxane or tetrahydrofuran are used, and in particular dimethylformamide or mixtures thereof, the reaction generally taking place at a temperature of 0 to 30 ° C.

The reactions are carried out in the presence of a phosphonate (III) deprotonating agent. Suitable are alkali metal hydrides and alkali metal amides, in particular hydrides and amides of sodium and potassium, sodium or potassium salts of dimethyl sulfoxide, alkyllithium compounds such as n-butyllithium, or alkali metal alcoholates, preferably anhydrous anhydrous and sodium methanolate.

Alternatively, compounds of formula I may be prepared by subjecting a phosphonium salt of formula (IV) ch3 CH3 CH3 -ch-pO3x® ch3 ch3Θ wherein X is Antoni, preferably chlorine or bromine, to a Wittig reaction with benzaldehyde. with formula (V) R1

OHC —ft '\ -ÖR2 V

35 \ = / 5 8 G 2 5 where R1 and R2 have the same meaning as above.

The Wittig or Wittig-Horner reaction usually results in mixtures of sterically isomeric (E / Z) -olefins.

Mixtures of E / Z isomers with a higher proportion of the Z isomer are converted to mixtures with a higher proportion of the (E) isomer under the action of light on the olefinic double bond. The resulting (E / Z) -isomer mixtures, which now have a more preferred (E) -isomer content, preferably yield 10 pure (E) -compounds of formula I, primarily by crystallization or by a chromatographic method such as column chromatography or preparative HPL chromatography.

The carboxylic acid esters of the general formula I, i.e. the compounds in which R2 is an alkoxycarbonyl group, are, if desired, converted into the free phenols and their physiologically tolerable salts by ester hydrolysis. The hydrolysis is conveniently carried out in the presence of a diluent, for example a water-miscible ether such as 1,2-dimethoxyethane or tetrahydrofuran, or a lower aliphatic alcohol such as methanol, ethanol, propanol, isopropanol or butanol, optionally in the presence of water or mixtures of said solvents and water. . Preferred solvents are aqueous mixtures of ethanol or methanol, the reaction being carried out at a temperature between 20 ° C and the boiling point of the reaction mixture. The hydrolysis preferably takes place in the presence of alkali and alkaline earth metals, in particular sodium and potassium, hydroxides or carbonates.

Compounds of formula I wherein R 2 is an alkyl group may, if desired, be subjected to ether cleavage to give the corresponding free phenol.

Some of the compounds obtainable according to the invention have an acidic hydrogen atom and can therefore be converted into a physiologically acceptable, easily water-soluble salt by means of bases in a conventional manner. Suitable salts are, for example, ammonium, alkali metal salts, in particular sodium, potassium and lithium salts, alkaline earth metal salts, in particular calcium or magnesium salts, and suitable organic bases, such as lower alkylamines, e.g. methylamine, ethylamine or cyclohexylamine, or salts formed with substituted alkylamines such as diethanolamine, triethanolamine 10 or tris (hydroxymethyl) aminomethane, and piperidine or morpholine.

Due to their pharmacological properties, the compounds according to the invention and their physiologically acceptable salts can be used for the local and systemic treatment of skin, mucosal and visceral precursors and cancer, as well as for prophylaxis and acne, psoriasis and other rheumatic diseases. , for the local and systemic treatment of inflammatory or degenerative changes in muscles, tendons and other parts of the musculoskeletal system. In addition to skin diseases, the preferred indication is the prophylactic and therapeutic treatment of precursors and tumors of cancer.

The pharmacological effects can be demonstrated, for example, according to the following experimental models: The compounds of the formula I arrest the keratinization due to vitamin A deficiency in hamster tracheal tissue in vitro. Keratinization is a precursor to carcinogenesis which is inhibited by the compounds of formula I according to the invention in a similar method in vivo when keratinization is initiated by chemical compounds, energy irradiation or viral cellular changes. This methodology is described in Cancer Res., 36 (1976), pp. 964-972; 7 ί5 8 G 2 5

Nature, 250 (1974), pp. 64-66; Nature, 253 (1975), p.

47 - 50; and Cancer Res., 43 (1983), 24695.

In addition, the compounds of the invention inhibit the rates of li-5 regulation of certain malignantly altered cells. This methodology is apparent from J. Natl. Cancer Inst., 60 (1978), pp. 1035-1041; Experimental Cell Research, 117 (1978), pp. 15-22; and Proc. Natl. Acad. Sci., USA, 77 (1980), pp. 2937-2940.

The adequate antiart-10 activity of the compounds of the invention can be determined in a conventional manner in animal experiments with an adjuvant arthritis assay or a streptococcal cell wall-induced arthritis assay. This methodology is described, for example, in Retinoids, Differentiation and Disease, Ciba Foundation Symposium 113, Pitman, 15 London, 1985, pp. 191-211.

Dermatological activity, for example in the treatment of acne, can be demonstrated e.g. comedolytic activity and the extent to which the compounds are able to reduce the number of vesicular tumors in the Rhino-20 mouse experiment.

This method has been described by Kligman et al. in The Journal of Investigative Dermatology, 73 ./. (1978), pp. 354-358.

: The compounds of formula I may be formulated into therapeutic agents or preparations using conventional liquid or solid carriers or diluents and commonly used pharmaceutical excipients in accordance with the intended use and suitable dosage in a conventional manner, for example by combining the active ingredient in such preparations with solid or conventional preparations. carriers and excipients.

These agents can be administered orally, parenterally or topically, respectively. Such preparations include, for example, tablets, shell tablets, granules, 8 o o P o c

Λ O U Δ. D

capsules, pills, powders, solutions or suspensions, solutions for infusion or injection, and pastes, ointments, gels, creams, lotions, powders, solutions or emulsions and sprays.

Therapeutic agents may contain the compounds of the invention when used topically in a concentration of 0.001 to 1%, preferably 0.001 to 0.1%, and for systemic use, preferably in a single dose of 0.1 to 50 mg, and may be used in one or more doses per day. depending on the nature and severity of the diseases.

Commonly used pharmaceutical excipients for topical use include alcohols such as isopropanol, oxyethylated castor oil or oxyethylated hydrogenated castor oil, polyacrylic acid, Gly serol monostearate, paraffin oil, petrolatum, wool grease, polyethylene glycol, polyethylene glycol, polyethylene glycol , for systemic use milk sugar, propylene glycol and ethanol, starch, talc, polyvinylpyrrolidone. If necessary, an antioxidant can be added to the preparations, for example tocopherol and butylated hydroxyanisole or butylated. . '. hydroxytoluene, or flavoring agents, stabilizers, emulsifiers, leveling agents, etc. It is a condition that all the substances used in the preparation of the pharmaceutical preparations are toxicologically acceptable and compatible with the active ingredients used.

Example 1 Method A: (E) -1- (4-Methoxyphenyl) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) propylene To a suspension of 6 g (0.2 mol) of sodium hydride (80%, first separated with petroleum ether from a 20-35% paraffin fraction) in 200 ml of absolute gn SO 2 5 tetrahydrofuran were added dropwise at 40-50 ° C. consisting of 100.4 g (0.18 mol) of 1- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) ethyltriphenylphosphonium bromide in 300 ml of absolute dimethyl-5-sulfoxide. After stirring for a further 0.5 hour until gas evolution ceased, a further 50 ml of tetrahydrofuran and 21.7 g (0.16 mol) of 4-methoxybenzaldehyde dissolved in 80 ml of tetrahydrofuran were added dropwise at about 30 ° C over a period of 20 minutes. After stirring overnight, the mixture was poured into 1 liter of water and extracted three times with ether. The combined ether layers were washed once with water, dried over Na 2 SO 4 and evaporated. The semi-crystalline residue (102.0 g) was heated in 600 ml of n-heptane to the boiling point of the mixture and cooled again. The solid (mainly triphenylphosphine oxide) was removed by filtration and the filtrate was evaporated. The residue was recrystallized from 550 ml of methanol. After drying, 26.4 g of the title compound were obtained, m.p. 103 - 104 eC.

20 Method B:

To a solution of 26.3 g (0.1 mol) of diethyl ester of p-methoxybenzylphosphonic acid in 400 ml of absolute dimethylformamide was added under nitrogen and; 11.5 g (0.1 mol) of potassium tert-butolate in portions at room temperature. After stirring for a further 30 minutes, 11.5 g (0.05 mol) of 2-acetyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene dissolved in 100 ml of abs were added dropwise at room temperature. . dimethylformamide. The mixture was then stirred for 4 hours at 60 ° C and for another 4 hours at 80 ° C. After cooling, the mixture was poured into 1 liter of ice water and extracted three times with ether, which was used 80 ml each time. To facilitate extraction, the mixture was acidified. The combined ether extracts were washed with five 200 mL portions of H 2 O, dried (MgSO 4) and evaporated. The residue was triturated with methanol ': CJ Γ · f' · Γ 10 and left to stand at -20 ° C (freezer). The next day, the crystals were separated by suction filtration. After drying, 6 g of the title compound was thus obtained, which was identical in physical properties to the compound prepared by Method A.

Example 2 (E) -1- (4-Butoxyphenyl) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) propylene In analogy to Example 1, 6 g (0.2 mol) of sodium hydride (80%), 100.4 g (0.18 mol) of 1- (5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthalenyl) ethyltriphenylphosphonium bromide α 28.5 g (0.16 mol) of 4-tert-butoxybenzaldehyde 1.5 g of the title compound, m.p. 107-108 ° C. The crude crystals remaining from the heptane extraction were pre-purified by flash chromatography (150 g Kieselgel 60, 60-230 mesh; n-heptane) and finally recrystallized from tetrahydrofuran / ethanol / methanol (2: 1: 8):

Example 3 20 (E) -5- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-propenyl] -1,3-benzodioxole In analogy to Example 1 gave 1.5 g (0.05 mol) of sodium hydride (80%), 25.1 g (0.045 mol) of 1- (5,6,7,8-tetrahydro-5.5 , 8,8-tetramethyl-2-naphthalen-25-yl) ethyltriphenylphosphonium bromide and 6.0 g (0.04 mol) of piperonal 4.3 g of the title compound, m.p. 90-91 ° C. Example 4 (E) -4- [2- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-propenyl] phenoxyacetic acid ethyl ester

In analogy to Example 1, 1.5 g (0.05 mol) of sodium hydride (80%) were obtained, 25.1 g (0.045 mol) of 1- (5,6,7,8-tetrahydro-5 , 5,8,8-tetramethyl-2-naphthalenyl Ethyltriphenylphosphonium bromide and 8.3 g (0.04 to 35 mol) of ethyl ester of 4-formylphenoxyacetic acid 2.5 g of the compound of m.p. 71-73 DEG C. The oily crude product remaining from the heptane extraction was pre-purified by flash chromatography (200 g Kieselgel 60, 230-400 mesh; n-heptane + 1% ethyl acetate) and finally recrystallized from methanol-ethanol / ethanol (1: 3). ).

Example 5 (E) -1- (3,4-Diacetoxyphenyl) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) propene In analogy to Example 1 from 3.0 g of 0.1 mol) of sodium hydride (80%), 50.4 g (0.09 mol) of 1- (5,6,7,8-tetrahydro-5, 5,8,8-tetramethyl-2-naphthalenyl) ethyltriphenylphosphonium bromide and 15.2 g (0.08 mol) of 3,4-diacetoxybenzaldehyde 7.0 g of the title compound, m.p. 135-137 ° C.

Example 6 (E) -1- (4-hydroxyphenyl) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) propene 3.8 g (11 mmol) ) (E) -1- (4-methoxyphenyl) -2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) propene obtained in Example 1 was suspended in 50 ml in methanol saturated with hydrogen chloride and stirred for 20 minutes at 60 ° C. The reaction solution was then poured into about 150 ml of ice water and extracted with three 100 ml portions of methyl tert-butyl ether. The organic phase was washed with two 100 ml portions of saturated sodium chloride solution and twice with water. After drying over Na 2 SO 4 and evaporation, 4 g of crude solid remain. Recrystallization from isopropanol gave 1.5 g of the title compound, m.p. 138 - 140 eC.

Example 7 (E) -4- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) -1-propenyl] phenoxyacetic acid 1.6 g (4 mmol) ) (E) -4- [2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl-35-1-propenyl] phenoxyacetic acid ethyl ester obtained in Example 4 and 0.5 g (8 · ': oor> r *

12 · 'ϋ U ^ D

mmol) of potassium hydroxide (85%) was heated under reflux in a mixture of 20 ml of ethanol and 1 ml of water. The mixture was then cooled, poured into 100% water and acidified with dilute HCl. After some time, a crystalline precipitate formed which was separated by suction filtration and washed with water and a small amount of ice-cold methanol. After drying, 1.2 g of the title compound were obtained, m.p. 152-154 ° C.

Claims (4)

CH 3 CH 2 or 2 wherein R 1 is a hydrogen atom or a C 1-4 alkanoyloxy group and R 2 is a hydrogen atom, a C 1-4 alkyl group or a C 1-4 alkanoyl group optionally substituted by a carboxyl or C 1-4 alkoxycarbonyl group, or R 1 and R 2 together represent a group - CH2-O-, as well as their physiologically acceptable salts, characterized in that a) the carbonyl compound of the formula (II) 20 ch3 ch3 ch3 25: ·: CH3 CH3 is reacted according to the Wittig-Horner reaction at -20 to 100 ° C with a phosphorus compound of formula (III) 30 R103R0R0 R2O - $ V-ch2—. \ = / 2 ^ OR4: 35 ΛΑ 1 'Ο Γ · · "14 υ U c. D wherein R1 and R2 are as defined above and R3 and R4 are C1-4alkyl, or b) a phosphonium salt of formula (IV ) 5 ch3 .ch3 <~ h3 -ch-p03x9 yyy CH.CHn 10 3 3 n wherein X is an anion, preferably chlorine or bromine, is subjected to a Wittig reaction with benzaldehyde of formula (V) 15. R 1 OHC-ft--R 2 V wherein R 1 and R 2 are as defined above, and optionally thereafter ester hydrolysis is performed on the alkoxycarbonyl group in the substituent R 2 or cleavage of the ether on a compound of formula I wherein R 2 is an alkyl group, and / or converting the obtained compound into a physiologically acceptable salt in a conventional manner. 'OPO £ 15. o UL · b For the production of therapeutically active vinylphenolIvat Raed formuleln (I) CH3 CH3 CH3 ζΦ'Ία -, 10 ch3 ch3 v or2 color R1 is not a hydrogen atom or a C1-4 alkanoyloxy group and R2 is a hydrogen atom, and optionally with a carboxyl or C 1-4 alkoxycarbonyl group substituted with a C 1-4 alkyl group or a C 1-4 alkanoyl group, or R 1 and R 2 are the same as the group -CH 2 -O-, as well as physiologically selected from the group consisting of , a) with carbonylation of formula (II) 20 ch3 ch3 ch3 ::: 25 ch3 ch3 of the Wittig-Horner reaction between -20 - 100 * C with phosphorus formation of formula (III) 30 R \ 0 0R3 r2 ° 4 \ - / X0R III 35 16 '' 8 u c. 5 color R1 and R2 are selected from the group consisting of ova and R3 and R4 are selected from the group consisting of C1-6 alkyl groups, or b) that the phosphonium salt is of formula (IV) 5 CH3 CH3 CH3 -CH-POX® QCt ,, CH3 CH3 10 Q color X is an anion, derived from chlorine or bromine, is a Wittig reaction with benzaldehyde from form- (V) 1 R1 15 OHC— ^ ~~ ^ -ÖR2 V color R1 and R2 are selected from the group consisting of esters of ester hydrolysis of an alkoxycarbonyl group 20 and substituents R2 or ethers of a compound of formula I, color R2 and an alkyl group, och / eller omvand-las den erhällna föreningen pä ett sedvanligt sätt account ett physiologiskt godtagbart sait.